1. Field of the Invention
The present invention relates to methods of enhancing the bio-availability of coenzyme Q10, and supporting the cardiovascular system, and a composition including coenzyme Q10, lactoferrin and/or angiogenin for use in the described methods, for multi-functional health applications.
2. Description of the Related Art
Coenzyme Q10 (CoQ-10) is a fundamental molecule for production of cellular energy in most living organisms. It is a fat-soluble quinone (chemical nomenclature: 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone, CAS registry no. 303-98-0), structurally similar to vitamin K and known by the names ubiquinone, ubidecarenone, neuquinone, and vitamin-Q.
Although found in all human cells, CoQ-10 occurs at relatively elevated concentrations in cells with high energy requirements such as heart, liver, muscle, and pancreas. The total body content of CoQ-10 has been estimated at 0.5-1.5 g. Normal blood levels range from 0.7-1.0 μg/mL. Human cells synthesize CoQ-10 from the amino acid tyrosine, in an eight-step aromatic pathway, requiring adequate levels of vitamins such as folic acid, niacin, riboflavin, and pyridoxine. A nutritional deficiency in any of these precursors would lead to CoQ-10 deficiency. [Folkers K. Relevance of the biosynthesis of coenzyme Q10 and the four bases of DNA as a rationale for the molecular causes of cancer and a therapy. Biochem Biophys Res Commun 224:358-61, 1996].
CoQ-10 is located in the inner mitochondrial membrane. It is a cofactor for at least three mitochondrial enzymes (complexes I, II and III) that plays a vital role in oxidative phosphorylation. It functions as the only non-protein component of the electron transport chain (ETC). This unique characteristic enables CoQ-10 to move and transfer electrons between flavoproteins and cytochromes. Each pair of electrons processed by the ETC must first interact with CoQ10, which is considered the central rate-limiting factor for the mitochondrial respiratory chain. Therefore, CoQ10 plays an essential role in adenosine triphosphate (ATP) or biological energy production. [Levin B. Coenzyme Q: clinical monograph. Quart Rev Nat Med 3:235-249, 1994; Crane F L, Sun I L, Sun E E. The essential functions of coenzyme Q. Clin Investig 71:S55-59, 1993].
CoQ-10 is located in membranes that are in close proximity to the unsaturated lipid chains, to act as a primary scavenger of free radicals. The concentration of CoQ-10 in many such membranes is high, about 3 to 30 times more than the tocopherol content. Since much of the CoQ-10 in cell membranes is in the quinol form, it works as a potent antioxidant to scavenge free radicals, as well as inhibit lipid and protein peroxidation. CoQ-10 constantly undergoes oxidation-reduction recycling. The reduced form readily donates electrons to neutralize oxidants and displays strongest antioxidant activity. CoQ-10 is the only known naturally occurring lipid-soluble antioxidant that regenerates to its active form in the body. [Quinn P J, et al. Expansion of the antioxidant function of vitamin E by coenzyme Q. Biofactors 9: 149-154, 1999]
The membrane stabilizing property of CoQ-10 has been postulated to involve the phospholipid-protein interaction that increases prostaglandin metabolism. CoQ-10 stabilizes myocardial calcium-dependent ion channels and prevents the depletion of metabolites essential for ATP synthesis. CoQ-10 also decreases blood viscosity, and improves blood flow to cardiac muscle in patients with ischemic heart disease. [Rauchova H, et al. Function of coenzyme Q in the cell: Some biochemical and physiological properties. Physiol Res 44:209-216, 1995; Kato T, et al. Reduction in blood viscosity by treatment with coenzyme Q10 in patients with ischemic heart disease. Int J Clin Pharmacol Ther Toxicol 28:123-126, 1990].
A vital role in the production of cellular energy combined with its potent antioxidant activity makes CoQ-10 an essential health supplement. Furthermore, its multifunctional properties including vitamin-like adjuvant activity, protection against age-related degeneration, support of homeostasis, prophylactic and therapeutic effects against several diseases, makes CoQ-10 an important nutraceutical agent.
The benefits of CoQ-10 supplementation are compelling in the protective and therapeutic management of cardiovascular health. Several controlled studies have reported the clinical efficacy of CoQ-10 as a supplemental therapeutic in the treatment of congestive heart failure (CHF). Myocardial tissue levels of CoQ-10 in CHF patients is about 33% lower than control subjects. Accordingly, the severity of symptoms associated with CHF and the presence of dilated cardiomyopathy strongly correlate with the degree of CoQ-10 deficiency. The proposed mechanism of CoQ-10 activity to alleviate symptoms of CHF is by a positive inotropic action. Such activity increases the contractile force of the heart and thereby improves cardiac output. Several conventional CHF therapeutics also possess this positive inotropic property, however, an adequate supply of cellular energy is necessary for optimal contractility of the heart. Failed hearts are ATP deficient; therefore, the reason behind CoQ-10 supplementation during CHF therapy is to improve bioenergetics of the cardiac tissue. Furthermore, any improved tolerance to aerobic exercise is attributed to the ability of CoQ-10 to maintain oxidative phosphorylation and act as a direct cardio-protectant through ATP production. In 1974, the Japanese Government has approved CoQ-10 for the treatment of cardiovascular disease, leading to its use by more than 12 million Japanese adults today. In addition, the use of CoQ-10 has also been widely advocated by healthcare professionals throughout the United States and Europe. [Mortensen S A, et al. Coenzyme Q10—clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tiss Reac 12:155-162, 1990; Mortensen S A. Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone). Clin Investig 71:S116-123, 1993].
Another widespread replenishment of CoQ-10 is in the clinical management of hypertension associated with deficiencies of succinate dehydrogenase and CoQ-10 reductase activity. Accordingly, reversal of CoQ-10 deficiency by dietary replenishment seems to control hypertension with reductions in systolic and diastolic blood pressure. [Greenberg S, Frishman W H. Coenzyme Q10—A new drug for cardiovascular disease. J Clin Pharmacol 30:596-608, 1990; Yamagami T, Shibata W, Folkers K. Bioenergetics in clinical medicine. Studies on coenzyme Q10 and essential hypertension. Res Commun Chem Pathol Pharmacol 11:273-288, 1975; Yamagami T, Shibata W, Folkers K. Bioenergetics in clinical medicine. VIII. Administration of coenzyme Q10 to patients with essential hypertension. Res Commun Chem Pathol Pharmacol 14:721-727, 1976].
Yet another common application of CoQ-10 is as an active adjuvant to rectify (balance) coenzyme deficiency that builds-up during long-term usage of certain medications. Lipid-lowering drugs (“statins”) such as lovastatin, simvastatin, pravastatin and gemfibrozil cause a decrease in serum CoQ-10 levels, which might predispose serious cardiovascular conditions. Therefore, it is advisable to use CoQ-10 supplement with prescription of statins, to protect individuals from risks associated with cardiac dysfunction. Beta-blockers (drugs that slow down heart rate and lower blood pressure) could also decrease the endogenous CoQ-10 levels by inhibition of CoQ-10-dependent enzymes. Also, certain oral hypoglycemic agents such as glyburide, acetohexamide, and tolazamide could decrease plasma CoQ-10 levels. CoQ-10 supplementation has been reported to reduce insulin requirements in diabetes mellitus. Therefore, diabetic patients taking CoQ-10 might require dosage adjustments of hypoglycemic agents. [Kaikkonen J, et al. Determinants of plasma coenzyme Q10 in humans. FEBS Lett 443:163-166, 1999; Thibault A, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 2:483-491, 1996; Pepping J. Coenzyme Q. Am J Health-System Pharm 56:519-521, 1999; Kishi T, et al. Bioenergetics in clinical medicine. Studies on coenzyme Q and diabetes mellitus. J Med 7:307-321, 1976].
Generally, individuals intending to boost physiological CoQ-10 levels consume this coenzyme as a dietary supplement in various forms, such as soft gels (most popular delivery format), capsules, tablets, powders or liquids. Regular doses of 30-60 mg/day (approximately 1 mg/kg of body weight) are generally recommended to prevent CoQ-10 deficiency and to maintain normal serum concentrations of 0.7-1.0 μg/mL. Therapeutic doses of 100-200 mg/day are recommended in the treatment of chronic heart disease. These higher doses may achieve serum concentrations of 2.0-3.0 μg/mL, in order to provide a positive impact on cardiovascular health. Divided doses have also been used to minimize adverse effects (if any) when the supplementation exceeds 100 mg/day. [Pepping J. Coenzyme Q10. Am J Health-Syst Pharm 56:519-521, 1999].
The metabolic fate and physiological turnover of CoQ-10 supplemented through the diet has not been fully elucidated. Early studies have indicated that peak levels of CoQ-10 in the plasma are attained within 5-10 hours following oral administration. After intestinal absorption, CoQ-10 is initially sequestered by chylomicrons, transferred to the liver and incorporated into the very low density lipoproteins (VLDL). The elimination half-life of CoQ-10 is approximately 34 hours and its excretion is primarily through the biliary tract. [Greenberg S, Frishman W H. Coenzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 30:596-608, 1990].
Reduced bioavailability due to poor intestinal absorption is a major limitation to use CoQ-10 as a health supplement. Several factors in the gastrointestinal milieu such as inflammatory conditions, pH, and mucosal brush border status markedly influence the CoQ-10 absorption. Accordingly, more than 60% of the orally administered CoQ-10 is excreted in the feces.
Isoprenoid side-chain in the quinone structure makes CoQ-10 an extremely lipophilic molecule. Therefore, when administered in the form of an oil solution or some kind of water and/or oil suspension or emulsion, lipophilic compounds usually show a poor bioavailability, which results in low concentration and a long build-up time of the compound in the systemic circulation. Therefore, it is highly critical to develop effective methods to overcome this set back, which is inherent to CoQ-10.
Several attempts to reduce the dosage quantities, and enhance bioavailability of CoQ-10 with solubility-enhancing agents have been reported. For instance, U.S. Pat. No. 4,824,669 describes a soft gel capsule with CoQ-10 and at least one vegetable oil carrier. This formula claims to increase blood basal levels of CoQ-10 to 2.5 g/mL in comparison to 1.6 g/mL from an equivalent 100 mg dose of a dry powder formulation. U.S. Pat. No. 4,483,873 discloses aqueous solutions of hydrogenated lecithin to increase CoQ-10 bioavailability. U.S. Pat. No. 6,045,826 discloses water-soluble compositions of CoQ-10 with a single solubilizing agent containing both hydrophobic and hydrophilic moieties. U.S. Pat. Nos. 6,056,971 and 6,441,050 disclose methods to solubilize CoQ-10 in a softgel, by mixing with an edible polyhydric alcohol solvent. U.S. Pat. No. 6,300,377 teaches about a CoQ-10 composition that omits polyhydric alcohol, but includes other agents to help improve solubility, including a glyceryl ester molecule having one to three C2 to C7 acyl groups. U.S. Pat. No. 6,623,734 utilizes medium chain triglycerides or “GelOil SC (a thixatropic gelatine composition)” as carriers. U.S. Pat. No. 6,740,338 discloses a method to use a lipid-soluble reducing agent (eg. ascorbyl palmitate) to maintain CoQ-10 in reduced state as ubiqinol for enhanced bioavailability.
While many patents and different formulations claim increased bioavailability of CoQ-10, the data supporting these claims are often inconclusive. Despite the continuing efforts to enhance the chemical solubility, the issue of limited intestinal diffusion of CoQ-10 continues to plague its applications as a broad-spectrum health supplement. There is a global necessity to develop an effective system to boost the intestinal assimilation of CoQ-10, preferably by active transport mechanisms, to augment its bioavailability for various cellular functions.
The physiological consequence of CoQ-10 supplementation intended for cardiovascular support also needs an in-depth scientific evaluation. In other words, the structure-function compatibility of a CoQ-10 replenishment to generate high cellular energy (strong “exogenous functional boost”) with a compromised cardiovascular matrix (weak “endogenous structural frame”) such as in an elderly or diseased individual requires a careful pharmacological assessment.
It should be noted that the physiological levels of CoQ-10 decline with age, in order to establish a ‘natural balance’ between the bioenergetics and the cellular degeneration. Plasma CoQ-10 concentration reach peak levels at 19-21 years of age and plummets down to 65% by age 80. CoQ-10 deficiency is prevalent among patients with congestive heart failure (CHF), cardiomyopathy, and chronic obstructive pulmonary disease (COPD). Certain individuals may experience premature decline in CoQ-10 levels or suffer from a disorder or condition that hinders CoQ-10 synthesis. Such CoQ-10 deficiencies may develop with long-term drug use while treating blood disorders such as hyper-lipidemia (eg. statins to reduce cholesterol), hypertension (eg. beta-blockers to control blood pressure), and diabetes (eg. sulfonylurea-type to regulate blood sugar). All of the above clinical conditions are manifested by severe fatigue and lack of energy.
In order to establish a physiological balance between cardiovascular condition and cellular energy requirements, it is necessary to promote regeneration of cardiac muscles (“angiogenesis”) and reinforce the vascular tissue (“vasculogenesis”). Therefore, the boosting of cellular energy with CoQ-10 supplementation, especially during the management of cardiovascular health, it becomes critically important that the underlying cellular-matrix is strengthened using in vivo stimulants of angiogenesis and vasculogenesis. This fundamental approach of ‘structure-functional’ balancing of CoQ-10 for human health applications has neither been addressed nor reduced to practice by nutritional or pharmaceutical industry so far.
The present invention provides a novel solution that could significantly influence the global perspective of CoQ-10 applications for human and animal health.